HB-EGF is a paracrine growth stimulator for early tumor prestages in inflammation-associated hepatocarcinogenesis.
OBJECTIVE
We studied the impact of heparin-binding epidermal growth factor-like growth factor (HB-EGF) on inflammation-driven hepatocarcinogenesis.


METHODS
HB-EGF expression was determined by qRT-PCR and immunodetection in hepatocellular adenoma and carcinoma and in mesenchymal (MC) and parenchymal liver cells obtained from different models of inflammation. The functions of HB-EGF in early hepatocarcinogenesis were assessed in co-cultures of unaltered and initiated/premalignant hepatocytes.


RESULTS
In human and rat (pre)malignant liver lesions, HB-EGF levels were comparable to that of the surrounding tissue. In inflamed livers HB-EGF was expressed predominantly in MC and was further increased by pro-inflammatory lipopolysaccharide (LPS) or linoleic acid hydroperoxide (LOOH). In culture, DNA-replication occurred rather in initiated/premalignant than unaltered hepatocytes and was further elevated by LOOH- or LPS-stimulated MC-supernatants. The supernatant effects were abrogated by pre-incubation with HB-EGF-neutralizing antisera. HB-EGF itself induced DNA-replication and mitosis preferentially in the initiated/premalignant cells. When transducing hepatocytes with a dominant-negative ErbB1-construct, HB-EGF-induced DNA-replications were blocked completely in unaltered hepatocytes but incompletely in initiated/premalignant cells, which suggests elevated ErbB-mediated signal transduction in first stages of hepatocarcinogenesis.


CONCLUSIONS
Pro-inflammatory stimuli induce the release of HB-EGF from MC, which stimulates DNA-replication in initiated/premalignant hepatocytes. Similar mechanisms may contribute to carcinogenesis in human inflammatory liver diseases.
Sagmeister
Sandra
S
Department of Medicine I, Division: Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
Drucker
Claudia
C
Losert
Annemarie
A
Grusch
Michael
M
Daryabeigi
Anahita
A
Parzefall
Wolfram
W
Rohr-Udilova
Nataliya
N
Bichler
Christoph
C
Smedsrød
Bård
B
Kandioler
Daniela
D
Grünberger
Thomas
T
Wrba
Fritz
F
Schulte-Hermann
Rolf
R
Grasl-Kraupp
Bettina
B
D018248:Adenoma, Liver Cell / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D002455:Cell Division; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D018773:Genes, erbB-1 / Q000235:genetics; D066257:Heparin-binding EGF-like Growth Factor; D006505:Hepatitis / Q000276:immunology* / Q000473:pathology; D022781:Hepatocytes / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000276:immunology*; D008113:Liver Neoplasms / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008648:Mesoderm / Q000166:cytology; D008938:Mitosis; D009367:Neoplasm Staging; D019899:Paracrine Communication / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured
C587883:HBEGF protein, human; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins